Most of an oral glucose load is taken up by muscle in man. Animal models for insulin resistance have reduced muscle glycogen synthase activity. In an effort to determine the importance of this enzyme to insulin mediated glucose disposal in man, we have measured the changes in muscle glycogen synthase activity with acute and chronic changes in insulin mediated glucose disposal. Following glycogen depletion both glycogen synthase activity and glucose disposal rates increased. Following overnutrition both glycogen synthase activity and glucose disposal rates decreased. In a study of subjects which were glucose tolerant or had varying degrees of glocuse intolerance, insulin mediated glucose disposal rates correlated with the glycogen synthase activity measured after insulin infusion. These data indicate a possible importance of regulation of glycogen synthase activity to insulin mediated glucose disposal rates.